Abstract:
:Many human cancers show constitutive or amplified expression of the transcriptional regulator and oncoprotein Myc, making Myc a potential target for therapeutic intervention. Here we report the down-regulation of Myc activity by reducing the availability of Max, the essential dimerization partner of Myc. Max is expressed constitutively and can form unstable homodimers. We have isolated stabilizers of the Max homodimer by applying virtual ligand screening (VLS) to identify specific binding pockets for small molecule interactors. Candidate compounds found by VLS were screened by fluorescence resonance energy transfer, and from these screens emerged a potent, specific stabilizer of the Max homodimer. In vitro binding assays demonstrated that the stabilizer enhances the formation of the Max-Max homodimer and interferes with the heterodimerization of Myc and Max in a dose-dependent manner. Furthermore, this compound interferes with Myc-induced oncogenic transformation, Myc-dependent cell growth, and Myc-mediated transcriptional activation. The Max-Max stabilizer can be considered a lead compound for the development of inhibitors of the Myc network.
journal_name
Mol Pharmacoljournal_title
Molecular pharmacologyauthors
Jiang H,Bower KE,Beuscher AE 4th,Zhou B,Bobkov AA,Olson AJ,Vogt PKdoi
10.1124/mol.109.054858subject
Has Abstractpub_date
2009-09-01 00:00:00pages
491-502issue
3eissn
0026-895Xissn
1521-0111pii
mol.109.054858journal_volume
76pub_type
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